In recent years, successive cloning studies of the glutamate receptor gene have been conducted, with the finding that glutamate receptors have a surprisingly large number of subtypes. At present, glutamate receptors are generally divided into two categories: “ionotropic receptors having an ionic channel structure” and “metabotropic receptors coupled with G-protein” (Science, 258, 597–603, 1992). Further, ionotropic receptors are divided into the following three pharmacological groups: N-methyl-D-aspartic acid (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainate (Science, 258, 597–603, 1992), while metabotropic receptors are divided into 8 groups (type 1 to type 8) (J. Neurosci., 13, 1372–1378, 1993; Neuropharmacol., 34, 1–26, 1995).
Also, metabotropic glutamate receptors are divided into three pharmacological groups. Among them, group II receptors (mGluR2/mGluR3) bind to adenylate cyclase and inhibit forskolin-stimulated accumulation of cyclic adenosine monophosphate (cAMP) (Trends Pharmacol. Sci., 14, 13 (1993)). Thus, it can be concluded that compounds acting as antagonists of group II metabotropic glutamate receptors would be effective for treating or preventing acute and chronic psychiatric and neurological diseases.
An object of the present invention is to provide a drug that is effective for treating and preventing psychiatric disorders such as schizophrenia, anxiety and its associated diseases, bipolar disorder and epilepsy, as well as neurological diseases such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia associated with muscular stiffness, cerebral ischemia, cerebral failure, myelopathy and head trauma, wherein the drug acts as an antagonist of group II metabotropic glutamate receptors.
On the other hand, selective serotonin reuptake inhibitors (SSRI), noradrenaline reuptake inhibitors and the like are known as antidepressants, but these inhibitors are not designed based on etiological considerations. Consequently, patients for whom such drugs are not effective are likely to continue to suffer symptoms of depression and experience a reduced quality of life. Thus, there exists a need to develop a drug that is based on etiological considerations, and that addresses a root cause of depressive symptoms.
Another object of the present invention is to provide a new type of antidepressant that is effective for treating and preventing depressive symptoms for which existing drugs are not effective.